title: Does hepatic oxidative stress enhance activation of nuclear factor-E2-related factor in patients with nonalcoholic steatohepatitis?
abstract: The imbalance of hepatic oxidant and antioxidant status is an important pathophysiological mechanism in nonalcoholic steatohepatitis (NASH). The nuclear factor-E2-related factor (Nrf2) is a key transcription factor regulating a plethora of antioxidant genes involved in antioxidant defense. To clarify the mechanisms of hepatic antioxidant defenses in human NASH, the aim of the current study was to examine oxidative stress-induced Nrf2 activation in the livers of patients with NASH. Liver biopsies were obtained from 19 NASH patients. Normal liver tissue was obtained from surgical resection specimens of 15 patients. The proportion of hepatocytes with 8-hydroxydeoxyguanosine (8-OHdG)-positive nuclei was increased in NASH livers compared with that in normal livers. Hepatic Nrf2 protein levels were increased with enhanced accumulation of hepatocellular nuclear Nrf2, which was positively correlated with that of 8-OHdG. Hepatic expression of γ-glutamylcysteine synthetase (γGCS), glutathione peroxidase 2 (GPx2), thioredoxin (TRX), and heme oxygenese 1 (HO-1), but not thioredoxin reductase 1 (TrxR1), was upregulated, and the protein levels of γGCS were positively correlated with those of Nrf2. Collectively, our findings lead to the hypothesis that oxidative stress may enhance Nrf2 activation in the livers of patients with NASH.
authors.affiliation: 1 Hepatology Division, Department of Internal Medicine, Hamamatsu University School of Medicine , Hamamatsu, Shizuoka, Japan .
authors.forename: Yurimi
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Kawata
authors.forename: Kinya
authors.initials: K
authors.lastname: Kawamura
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sumiyoshi
authors.forename: Hidenao
authors.initials: H
authors.lastname: Noritake
authors.forename: Shinya
authors.initials: S
authors.lastname: Watanabe
authors.forename: Takeshi
authors.initials: T
authors.lastname: Chida
authors.forename: Kenichi
authors.initials: K
authors.lastname: Souda
authors.forename: Takanori
authors.initials: T
authors.lastname: Sakaguchi
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Nakamura
authors.forename: Takafumi
authors.initials: T
authors.lastname: Suda
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000328:Adult; D000368:Aged; D000975:Antioxidants / Q000378:metabolism; D001706:Biopsy; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine